Benzofuran derivatives suitable as uv-absorbents



i States Patent M 9,5 lint. Cl. Ellid 5/40; A613 23/00; Hi h 1/2;

ABSTRACT F THE DHSCLOSURE 2-(2,4-dimethylphenyl)-benzofuran and 5, 6-,or 7- methyl derivatives thereof suitable for absorbing UV- radiation of290320 m and particularly useful as oilsoluble active ingredients forsun tan preparations and the like.

Applicants hereby claim the benefit of the filing date of German patentapplication M 69,570 of May 20, 1966.

This invention relates to novel derivatives of hemefuran, and moreparticularly to suntan preparations based n such derivatives.

Although there are many suntan preparations on the market, there arecertain disadvantageous properties of the conventional activeingredients incorporated therein. Consequently, there is a particularneed for active agents having better properties such as:

l 1) More selective UV-absorption characteristics, permitting tanning,but preventing sunburn;

(2) Higher oil solubilities, permitting more of the agent to beincorporated in the carrier; and

(3) Better resistance to light and heat, resulting in minimum rancidityand longer shelf life. I

An object of this invention, therefore, is to provide effective andnovel compounds suitable as improved UV- absorbents.

Another object is to provide processes and intermediates for theproduction of the novel compounds.

Still another object is to provide cosmetic preparations for theprevention of sunburn.

A still further object is to provide a process for absorbing and/orscreening out UV-radiation by directing a source of UV-radiation on anobject or mammal treated with a compound of this invention.

Upon further study of the specification and claims, other. objects andadvantages of the present invention will become apparent.

To attain the objects of this invention there are provided compounds ofthe following formula:

wherein: R R and R represent hydrogen or methyl, with the provision thatat least two of R R and R representhydrogen.

It has been discovered that compounds of Formula I are excellentUV-absorbers in the ultraviolet range of about 290-320 my, thewavelength range responsible for sunburns. For a'clearer understandingof this efiect. the absorption efficiency, measured in percenttransmisison,

Patented ru to, rare is tabulated below as a function of wavelength forthe following compounds:

Ia2-( 2,4-dimethylphenyl )-benzofuran lb--2-( 2,4-dimethylphenyl-5-rnethyl-benzofuran lc2-' 2,4-dimethylphenyl -6-methyl-benzofuranId--2-(2,4-dimethylphenyl)7-methyl-benzofurau In the following. table,the data are based on solutions of 1 mg. of active agent in 100 ml.isopropanol and a layer thickness of 1 cm.

Percent trnnsmiss ion Id Wavelength in ma derivatives thereof, asevidenced by the following tabu lated solubilities at 20 C.

DAB 6 [Deutsches Solubility in Arznel-Buch gJIOO g. 01 (German Compoundparatiin oll Drug 'Book)] Ia Ib Ic Id Still further advantages of thenovel agents of this invention as compared to conventional UV-abso'rbersare: odorlessness, low toxicity, resistance to light and atmosphericconditions, and chemical stability. This latter advantage isparticularly important inasmuch as the most common UV-absorbers arep-methoxycinnamic acid ethoxyethyl ester, p-dimethylaminobenzoic acidmethyl and glycerine esters, all being subject to hydrolysis orsaponification in time. The fact that the agents of this invention donot contain any ester groups eliminates the possibility of suchdecomposition reactions, thereby iii suring a uniform efiicaciousness.

T he specific compounds of Formula I are all novel and unobvious albeitthat German Patent 676,103 broadly describes an infinitely large classof compounds covering, inter alia, 2-aromatic-benzofurans.

For the production of suntan compositions, about 0.5 to 10, preferably 1to 5 parts by weight of the novel active agents of this invention areincorporated with parts by weight of a cosmetically acceptable carrier.

It is possible, for example, to produce, by the addition of salve orcream foundations and the like salves, ointments, pastes, and oilysolids. By mixture with solvents, if desired, also with emulsifiers,there can be produced liquid and aerosol preparations.

Suitable cosmetically acceptable carriers are, for example,hydrocarbons, such as solid or liquid paraffin, ceresin, montan wax;vegetable or animal oils and fats,

attain t such as olive oil, peanut oil, sesame oil, or almond oil; cocoabutter, beesu mineral Wax or carnauba wax, wool fat, spermaccti; fattyacids and fatty acid esters, such as stearic, palmitic, and oleic acids,glycerin monoor distearate, glycerin monooleate, isopropyl myristate,isopropyl stearate, butyl stearate; and ethyl, isopropyl, cetyl,stearyl, and palmityl alcohols. Moisturizing agents such as polyvalentalcohols, e.g. glycol, glycerine and sorbitol, are useful additives, Asliquids, either oil-inwater or water-in-oil systems can be used, usingcommercially available emulsifiers of the non-ionic, cationic, anionic,or ampholytic types. To liquid systems it is also usual to addthickeners, such as methyl, ethyl, or carboxymethyl cellulose,polyacrylic acid, tragacanth, agaragar, or gelatin. Furthermore, it is,of course, possible to add, if necessary or if desired, other additives,such as insect repellents, aerosol propellants, perfumes, preservatives,or physiologically compatible dyestuffs. Typical insect repellents are,for instance, the N,N-diethyl amides of caprylic and m-toluic acids,dimethyl phthalate, 2- ethyl-l,3-hexanediol, and butoxy polypropyleneglycol. Suitable aerosol propellants comprise trichlorofiuoromethane anddichlorodifiuoromethane, furthermore nitrogen, carbon dioxide, propane,and butane.

To avoid sunburn, an effective amount of the active agent must beapplied to the skin, this amount varying with the intensity and durationof the UV source, as Well as with the complexion of the persons skin. Ingeneral, however, it is estimated that an application of about 10 to 100mg. of active agent per 100 squart centimeters of skin surface shouldprevent sunburn for approximately 24 hours under direct midday summerlight radiating in the northern temperate zone. I

For general UV-screening use, the agents of this invention can also beincorporated with one or more other UV-absorbents, such asZ-phenylbenzimidazole-5-sulfonic acid sodium salt,3,4-dimethylphenylglyoxylic acid sodium salt, 4-phenylbenzophenone, andisooctyl-4-phenylbenzophenone-2carboxylate.

The compounds of Formula I can be produced by standard reactions. Forexample, they can be obtained by reacting phenol (or 0-, m-, orp-cresol) with chloroacetic acid to form phenoxyacetic acid (or o-, m-,or ptolyloxyacetic acid); conversion of the thus-obtained product (forexample, with thionyl chloride) into the corresponding acid halogenides"(for example, phenoxyacetyl chloride);, Priedel-Crafts reaction withm-Xylene (for example, in the presence of aluminum chloride) to obtain2,4-dimethyl-w-phenoxyacetophenone (or 2,4-dimethyl-o, -m-, or-p-tolyloxyacetophenone); and several hours of heating the same withpolyphosphoric acid to temperatures between l00 and 170 C,, preferablyabout 130 C., rearrangement taking place to2-(2,4-dimethylphenyl)--benzofurans.

The reaction products can likewise be obtained by re- I actingsalicylaldehyde (or 3-, 4-, or S-rnethyl-salicylalde hyde) with loweralkyl esters of wbrOmQ-(ZAdimethyI- phenyl)-acetic acid (preferably themethyl or ethyl ester thereof), subsequent saponification of thethus-obtained 2-(2,4-dimethylphenyl)-3-hydroxy 2,3dihydrobenzofuran-Z-carboxylic acid esters, as well as decarboxylationand dehydration.

Although the main field of application of the novel benzof'uranderivatives is the cosmetical one, the compounds are also useful fortechnical and industrial uses. Chemical compositions and articles ofmanufacture can be provided which are resistant to UV radiation. In thetechnical field of application, the compounds of the invention areparticularly advantageous for the inhibition of UV-initiateddeterioration of organic polymers, both natural and synthetic, includingpolyvinyl chloride, poly methacrylates, cellulose acetate, polystyrene,polyvinyl acetate, and polyolefins such as polyethylene andpolypropylene, and of common lacquers based on nitrocellu- 1 lose, airoroven-dried polyesters, epoxide resins, or polyol-diisocyanates Importantnovel intermediates in the process of manufacture of the novelbenzofurans include:

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative.

The numerical 'data in the following examples below are in parts byweight. In place of the active agent specifically set forth, 2-(2,4-dimethylphenyl)-benzofuran (Ia), it is possible to employ theabove-mentioned compounds Ib, Ic or Id. Furthermore, if desired or ifnecessary, additives can be incorporated (for example, perfume,dyestuffs, preservatives, etc.).

EXAMPLE 1 Suntan oil:

2-(2,4-dimethylphenyl)-benzofuran Z Parafiin oil 30 Refined peanut oil68 EXAMPLE 2 Suntan oil With repellent effect:

2-(2,4-dimethylphenyl)-benzofuran 3 Liquid parafiin 2O Isopropylmyrisfate 57 Caprylic acid diethyl amide 5 m-Toluic acid diethyl amide 5Dimethyl phthalate l0 EXAMPLE 3 Suntan cream:

2-(2,4-dimethylphenyl)-benzofuran 3 Sodium salt of Cetyl-stearyl sulfaten 2 Cetyl alcohol 1O Vaseline -1 20 Octadecyl alcohol 5 Spermaceti lGlycerin monostearate l Lanolin 1 Sorbitol solution, 70% 5 Water 47EXAMPLE 4 Suntan lotion:

2-(2,4-dimethylphenyl)-benzofuran 3.0 Liquid paraffin 10.0Polyoxyethylene ester of stearic acid 10.0 lsopropyl myristate 10.0Sorbitol solution, 70% 5.0 Sodium laurylether sulfate M 0.5 Water 61.5

Mixture of trichlorofiuoromethane and dichlorodifiuoromethane (70:30)(propellant gas) 20 EXAMPLE 7 Light-protective cream:

2-(2,4-dimethylphenyl)-benzofuran 2 2 phenyl benzimidazole-S-sulfonicacid-triethanolamine salt, 50% 3 Commercial cream base (system:oil/water or water/oil) 95 EXAMPLE 8 Lipsticks: 100 g. commerciallyavailable lipstick mass is melted, and 2 g. of2-(2,4-dimethylphenyl)-benzofuran are dissolved therein. The mass ispoured into cooled lipstick molds, and the molded articles are removedafter cooling.

The following examples demonstrate the production of the active agentsof this invention:

EXAMPLE A (a) 280 g. phenoxyacetyl chloride are dissolved in 830 ml.m-xylene; 155 g. aluminum chloride are added, and the mixture is heatedfor one hour under reflux conditions. After ice Water is added to thereaction mixture, the resultant xylene phase is separated, and theresultant aqueous phase is extracted with benzene. The solvents aredistilled from the combined solutions, and the residue is distilled at205-210" C./ 12 mm. There is thus obtained 273 g. ofa-phenoxy-2,4-dirnethylacetophenone.

Analogously, the following compounds can be produced:

with o-tolyloxyacetyl chloride: a-(2-methylphenoxy)-2,4-dimethyl-acetophenone, B.P. 220222 C./12 mm.;

with m-tolyloxyacetyl chloride: oc-(3-methylphenoxy)-2,4-dimethyl-acetophenone, B.P. 219221 C./12 mm;

with p-tolyloxyacetyl chloride: a-(4-methylphenoxy)-2,4-dimethyl-acetophenone, B.P. 223226 C./12 mm.

(b) 16.5 g. u-phenoxy-2,4-dimethyl-acetophenone and 165 g.polyphosphoric acid are heated to 132 C. for 2 hours with stirring. Thereaction mixture is then poured over ice water and extracted with ether;the resultant ether solution is washed with a solution of sodiumbicarbonate and dried over magnesium sulfate. After the solvent has beendistilled off, the residue is distilled at l95197 C./l2 mm. There isthus obtained 10 g. of

2-(2,4-dimethylphenyl)-benzofuran which melts, after recrystallizationfrom isopropanol, at 50-51 C.

Analogously, the following can be obtained:

2 (2,4 dimethylphenyl)-5-methyl-benzofuran, M.P. 67-

69 C.; B.P. 210215 C./12 mm.;

2 2,4 dimethylphenyl)-6-methyl-benzofuran, M.P. 80-

82 C. (from isopropanol);

2 (2,4-dimethylphenyl)-7-methyl-benzofuran, B.P. 200- 205 C./12 rnm.

EXAMPLE B (a) 25 g. salicylaldehyde and 50 g.u-bromo-(2,4-dimethylphenyl)-acetic acid ethyl ester are boiled for 4hours in 100 ml. methylethyl ketone with the addition of 32 g. anhydrouspotassium carbonate. The reaction mixture is cooled, diluted with ether,and filtered from the undissolved salt. The solvent is distilled fromthe filtrate, and the residue is degasified on a steam bath by a waterjet aspirator. The remaining product, 3hydroxy- 2 (2,4 dimethylphenyl)2,3-dihydrobenzofuran-Z-carboxylic acid ethyl ester, is mixed, withoutpurification, with 60 ml. 32% sodium hydroxide solution, and heated on asteam bath until the contents of the flask are solid. Then, the mixtureis vacuum-filtered; the residue is dissolved in water and acidified withconcentrated hydrochloric acid. The oil which separates is taken up inchloroform, washed with Water, dried, and the solvent is distilled off.There is thus obtained 30 g. 3-hydroxy-2-(2,4- dimethylphenyl) 2,3dihydrobenzofuran 2-carboxylic acid.

(b) 10 g. of the crude 3 hydroxy 2(2,4-dimethylphenyl)-2,3-dihydrobenzofuran-2-carboxylic acid areslurried up with 25 ml. water. Then, 10 ml. concentrated sulfuric acidis added, and the mixture is heated on a steam bath until thetermination of CO evolution. The thusobtained crude product isdistilled, thereby obtaining 8 g. of 2-(2,4-dimethylphenyl)-benzofuranhaving a boiling point of l97 C./12 mm. and a melting point of 5051 C.

The preceding examples can be repeated with similar success bysubstituting the generically and specifically described reactants andoperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention.

What is claimed is:

1. A compound of the formula:

R1 (EH3 wherein: R R and R represent hydrogen or methyl,

with the provision that at least two of R R and R represent hydrogen.

'2. A compound as defined by claim 1 wherein said compound is2-(2,4-dimethylphenyl)-benzofuran.

3. A compound as defined by claim 1 wherein said compound is 2 (2,4dimethylphenyl) S-methyl-benzofuran.

4. A compound as defined by claim 1 wherein said compound is 2 (2,4dimethylphenyl) 6-methyl-beuzofuran.

5. A compound as defined by claim 1 wherein said compound is 2 (2,4dimethylphenyl) 7-methy1-benzofuran.

References Cited FOREIGN PATENTS 1939 Germany.

OTHER REFERENCES ALEX MAZEL, Primary Examiner B. DENTZ, AssistantExaminer US. Cl. X.R.

